Bruchpilot Promotes Active Zone Assembly, Ca
            <sup>2+</sup>
            Channel Clustering, and Vesicle Release

Kittel, Robert J.; Wichmann, Carolin; Rasse, Tobias M.; Fouquet, Wernher; Schmidt, Manuela; Schmid, Andreas; Wagh, Dhananjay; Pawlu, Christian; Kellner, Robert R.; Willig, Katrin I.; Hell, Stefan W.; Buchner, Erich; Heckmann, Manfred; Sigrist, Stephan J.

doi:10.1126/science.1126308

Cited by 748 publications

(868 citation statements)

References 39 publications

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“…To test this, we quantified Nlg1 intensity (as a measure of Nlg1 clustering) in mutants for presynaptic brp (brp 1.3 ) 20 . The brp mutant larvae show a stronger decrease in presynaptic neurotransmitter release than any of the mutants discussed above 5,11,20,22,23 . Nlg1 clusters, however, were not reduced in brp mutants (Fig.…”

Section: Lam Gmentioning

confidence: 80%

“…Nlg1 clusters, however, were not reduced in brp mutants (Fig. 3c,d), indicating that the observed reduction of Nlg1 in Syd-1 and Nrx-1 mutants was neither due to reduced transmission nor a reflection of a general active zone assembly deficit (which is very pronounced in brp mutants 22 ). Instead, Syd-1 seems to be specifically involved in clustering postsynaptic Nlg1 adjacent to synapses.…”

Section: Lam Gmentioning

confidence: 87%

“…At control NMJs, diffraction-limited BRP spots mark individual active zones 21 that appear as ring-shaped structures when imaged at higher resolutions with STED 20,22 (Fig. 2g,h).…”

Section: Similar Synaptic Phenotypes Of Syd-1 Nrx-1 and Nlg1mentioning

confidence: 99%

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Cooperation of Syd-1 with Neurexin synchronizes pre- with postsynaptic assembly

et al. 2012

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Understanding the process of synapse assembly in molecular and cell-biological detail is a prerequisite for understanding neural circuit development and activity-mediated remodeling, and thus is important for unraveling learning and memory processes (structural plasticity) [1][2][3] . Functional chemical synapses are characterized by two apposed compartments that must be coestablished with high spatiotemporal precision: the presynaptic active zone, where regulated and rapid fusion of neurotransmitter-filled synaptic vesicles takes place, and the postsynaptic density (PSD), which embeds neurotransmitter receptors.Glutamatergic neuromuscular junction (NMJ) terminals of Drosophila larvae grow to meet the requirements of the growing muscle fibers, a process in which new synapses are continuously added 4 (where a synapse is defined as a single active zone opposed by a single PSD 1 ). In vivo imaging has shown that presynaptic Syd-1 and Liprin-α clusters initiate active zone formation 5 . On the postsynaptic side, initial PSD growth depends on incorporation of a glutamate receptor (GluR) containing the GluRIIA subunit. Later PSD maturation is marked by the incorporation of GluRIIB-containing receptor complexes 6 . Synapse assembly is concluded at presynaptic active zones by the incorporation of the active zone scaffold component Bruchpilot (BRP) 5 .Coordinating synapse assembly requires signaling across the synaptic cleft, which separates pre-from postsynaptic membranes. Transsynaptic cell adhesion molecules are obvious candidates for coupling active zone and PSD assembly. In vitro, the Neurexin-Neuroligin (Nrx-Nlg) complex can mediate the trans-synaptic signaling required for synapse assembly 7,8 . How this signaling axis integrates with the additional assembly machinery, however, has remained largely unclear.Here, we provide evidence of a dual role for Syd-1 in early assembly of NMJ synapses. It retains Liprin-α clusters at active zones and is important for clustering of presynaptic Nrx-1, likely through a direct and PDZ-domain-dependent interaction. Consequently, Syd-1 is also needed for clustering of postsynaptic Nlg1, which organizes postsynaptic assembly. Coincident action of Syd-1 with Nrx-1-Nlg1 appears to allow active zone scaffolds to pass through an initial, still fragile assembly phase. We suggest that binding between Syd-1 and Nrx-1-Nlg1 is a means to coordinate pre-with postsynaptic assembly. Our study shows an example of how coincident action of a presynaptic active zone scaffold protein and a trans-synaptic cell adhesion protein module can spatiotemporally orchestrate synapse assembly. RESULTSInitially described in cell culture systems (for a review, see ref. 9), interaction between mammalian presynaptic Nrx proteins and postsynaptic Nlg molecules was proposed to be important for proper synapse assembly. However, genetic ablation of three Nlg (Nlgn) genes in mice 10 does not result in a substantial structural phenotype, potentially reflecting a strong capacity for compensatory processes in vivo.Nonethe...

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Section: Lam Gmentioning

confidence: 80%

Section: Lam Gmentioning

confidence: 87%

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Cooperation of Syd-1 with Neurexin synchronizes pre- with postsynaptic assembly

et al. 2012

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“…The importance of the CAZ in orchestrating neurotransmitter release is further exemplified by the fact that flies with null alleles of BRP 29 show loss of the electron-dense active zone cytomatrix, a morphological defect that is correlated with impaired clustering of voltage-gated Ca 2+ channels and with desynchronization of glutamate release. Alterations in activity-dependent synaptic vesicle exocytosis are also seen upon knockdown of the giant CAZ protein piccolo 30 .…”

Section: Box 1 | Presynaptic Organization -Exocytic and Endocytic Zonesmentioning

confidence: 99%

“…Genetic analysis of presynaptic scaffolds has also turned out to be difficult because of the complex (broad) phenotypes resulting from null alleles. For example, deletion of the active zone component BRP in Drosophila melanogaster causes a severe loss of active zone dense bodies (T-bars) and a concomitant declustering of presynaptic Ca 2+ channels, provoking a severe deficit in baseline synaptic vesicle release 29 . A recent study 107 identified a hypomorphic allele termed brp nude , lacking merely the last 17 amino acids (that is, <1% of all residues) of BRP.…”

Section: Calcium Regulationmentioning

confidence: 99%

Protein scaffolds in the coupling of synaptic exocytosis and endocytosis

2011

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Communication between nerve cells largely occurs at chemical synapses -specialized sites of cell-cell contact where electrical signals trigger the exocytic release of neurotransmitter, which in turn activates postsynaptic receptor channels. The efficacy with which such chemical signals are transmitted is crucial for the functioning of the nervous system. Modulation of neurotransmission enables nerve cells to respond to a vast range of stimulus patterns. Synaptic activity can also be tremendously diverse; from the fast synapses of the hippocampus, to slow neuropeptide-containing synapses. Indeed, some signalling pathways are active in the absence of stimulation, such as those involved in the processing of sensory information, which transmit tonically at high rates of up to 100 Hz or more 1,2 .Intriguing questions arise from these facts, including how high rates of neurotransmission can be maintained over long periods of time, and what limits the ability of a given synapse to release neurotransmitter during sustained periods of activity. Recent data indicate that in many synapses, exocytosis of neurotransmitter is coupled to endocytosis, and that synapses have evolved a specialized apparatus of scaffolding proteins to comply with these demands. Such scaffolds aid the temporal and spatial coupling of exocytosis and endocytosis, and are crucial for maintaining rapid neurotransmission during sustained activity 3 .Exocytosis of neurotransmitter is triggered by stimulusinduced calcium influx into the nerve terminal 4,5 and the subsequent fusion of synaptic vesicles with the presynaptic plasma membrane at specialized regions called active zones (BOX 1). Exocytosed synaptic vesicle membrane proteins and lipids in turn are recycled at the endocytic or periactive zone (BOX 1) that surrounds the release site, to restore functional synaptic vesicle pools for reuse and to ensure long-term functionality of the synapse 6-8 (FIG. 1). Depending on the type of synapse and the stimulation frequency, several modes of endocytosis with different time constants -for example, fast and slow endocytosisseem to operate 7,9,10 . Clathrin-mediated endocytosis arguably represents the main pathway of synaptic vesicle endocytosis 6,8,11 , although other modes -for example, fast kiss-and-run exocytosis and endocytosis -could operate in parallel.Although the machineries for exocytic membrane fusion 12,13 and for endocytic retrieval of synaptic vesicle membranes have been studied separately in some detail 6,14 , comparatively little is known about the coupling between exocytosis and endocytosis. Here we synthesize recent data from physiological, morphological and biochemical studies in several model systems into hypothetical models for scaffold-based mechanisms underlying exocytic-endocytic coupling.The synaptic vesicle cycle Synaptic vesicle pools. Some defining features of chemical synapses are the presence of one or several clusters of synaptic vesicles in the presynaptic nerve terminal, and ultrastructural specializations at the pre-and postsy...

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Regulation of synaptic release‐site Ca²⁺ channel coupling as a mechanism to control release probability and short‐term plasticity

2018

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Synaptic transmission relies on the rapid fusion of neurotransmitter-containing synaptic vesicles (SVs), which happens in response to action potential (AP)-induced Ca influx at active zones (AZs). A highly conserved molecular machinery cooperates at SV-release sites to mediate SV plasma membrane attachment and maturation, Ca sensing, and membrane fusion. Despite this high degree of conservation, synapses - even within the same organism, organ or neuron - are highly diverse regarding the probability of APs to trigger SV fusion. Additionally, repetitive activation can lead to either strengthening or weakening of transmission. In this review, we discuss mechanisms controlling release probability and this short-term plasticity. We argue that an important layer of control is exerted by evolutionarily conserved AZ scaffolding proteins, which determine the coupling distance between SV fusion sites and voltage-gated Ca channels (VGCC) and, thereby, shape synapse-specific input/output behaviors. We propose that AZ-scaffold modifications may occur to adapt the coupling distance during synapse maturation and plastic regulation of synapse strength.

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Bruchpilot Promotes Active Zone Assembly, Ca ²⁺ Channel Clustering, and Vesicle Release

Cited by 748 publications

References 39 publications

Cooperation of Syd-1 with Neurexin synchronizes pre- with postsynaptic assembly

Cooperation of Syd-1 with Neurexin synchronizes pre- with postsynaptic assembly

Protein scaffolds in the coupling of synaptic exocytosis and endocytosis

Regulation of synaptic release‐site Ca²⁺ channel coupling as a mechanism to control release probability and short‐term plasticity

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Bruchpilot Promotes Active Zone Assembly, Ca 2+ Channel Clustering, and Vesicle Release

Cited by 748 publications

References 39 publications

Cooperation of Syd-1 with Neurexin synchronizes pre- with postsynaptic assembly

Cooperation of Syd-1 with Neurexin synchronizes pre- with postsynaptic assembly

Protein scaffolds in the coupling of synaptic exocytosis and endocytosis

Regulation of synaptic release‐site Ca2+ channel coupling as a mechanism to control release probability and short‐term plasticity

Contact Info

Product

Resources

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Bruchpilot Promotes Active Zone Assembly, Ca ²⁺ Channel Clustering, and Vesicle Release

Regulation of synaptic release‐site Ca²⁺ channel coupling as a mechanism to control release probability and short‐term plasticity